The initiation of the herpes simplex virus lytic replication cycle depends upon the coordinated expression of the viral (IE) immediate early genes. These genes are controlled by complex multiprotein enhancer assemblies that consists of viral and cellular components. Studies are designed to identify critical components and investigate their interactions and their biochemical functions in order to provide insights into the mechanisms that drive viral gene expression and lytic infection. The mammalian coactivator HCF-1 is one of the essential factors involved in both the assembly of the viral IE enhancer complex and the activation of IE gene transcription. Studies address functions of this coactivator during the viral lytic cycle as well as in normal cellular processes. The importance of both is underscored by the complex viral-cell interactions that impact the lytic and latent states of the viral life cycle. Previous studies have determined that HCF-1 functions as a component of chromatin modification complexes that are essential for modulating the chromatin status of the viral IE genes upon infection. Additionally, HCF-1 modulates chromatin during HSV-1 DNA replication indicating that the protein plays critical roles throughout the viral lytic replication cycle. In fiscal year 2017, additional HCF-1 associated complexes were identified that play critical roles in the viral IE gene regulatory paradigm and thus control viral lytic infection and reactivation from latency.